Process and 5-oxygenated intermediates for the manufacture of 19-norsteroids of the androstane series



United States Patent 3,175,014 PROCESS AND s-oXYGENArEn INTERMEDIATES FOR THE MANUFACTURE OF 19-N0RSTER0ID OF THE ANDROSTANE SERIES RaphaelPappo, Skokie, and Leonard N. Nysted, Highland Park, Ill., assignors toG. D. Searle & (10., Chicago, 111., a corporation of Delaware NoDrawing. Filed Feb. 6, 1964, Ser. No. 343,115 17 Claims. (Cl. 260-23955)The present invention relates to a novel process and novel intermediatesuseful in the manufacture of 19- norsteroids of the androstane series.Those intermediates are Sa-(lower alkanoyloxy)-6B-19-epoxy compoundswhich can be represented by the following structural formula CH O Z 9'wherein X and Z are symbolic of carbonyl, fl-hydroxy methylene, or,8-(lower alkanoyl)oxymethylene groups, and Y is a lower alkanoyloxyradical.

Exemplary of the lower alkanoyl radicals encompassed by the X, Y and Zterms are acetyl, propionyl, butyryl, valeryl, caproyl, and thebranched-chain groups isomeric therewith.

Preferred starting materials required for the conduct of the presentinvention are those substances represented by the structural formula CHCH wherein X can be either a carbonyl, ketalized carbonyl, or ,6-(loweralkanoyl)oxymethylene group. Those materials can be converted, typicallyby reaction with N- bromo-acetamide and perchloric acid in aqueoustetrahydrofuran, to the corresponding 5u,6fi-bromohydrins, whichsubstances are dehydrobrominated, suitably by means of potassium acetatein aqueous dioxane, resulting in formation of the 5,6,6fi-epoxy group.These processes are specifically illustrated by the conversion of3,8-acetoxyandrost-5-en-l7-one to3fl-actoxy-5a-bromo-6fi-hydroxyandrostan-17-one and dehydrobrominationof the latter substance to afford3B-acetoxy-5,6,6;3-epoxyandrostan-l7-one. These 5/3,6,8-epoxides can beconverted to the instant novel 5a-acetoxy-6fi,19-epoxy derivativesdirectly by oxidation with a suitable reagent such as lead tetraacetate,lead tetraacetate and iodine, mercuric acetate and iodine, or silveracetate and iodine, or by the alternate route of conversion first to the50,6fi-di0l S-acetate followed by oxidation with one of theaforementioned reagents. Thus, 3B-acetoxy-SB,6,8-epoxyandrostan-17-oneis contacted with lead tetraacetate and iodine in acetic acid to produce3/3,5m-diacetoxy-6B,19-epoxyandrostan- 17-one. Alternatively, the latter5,8,6/i-epoxide is con verted to3[3,5tx-diacetoxy-6,8-hydroxyandrostan-l7-one by reaction with aceticacid in the presence of p-toluenesulfonic acid, and that diacetate isoxidized to the corresponding 6,3,19-epoxide by reaction with leadtetraacetate O t (lower alkyl) 0 and iodine in acetic acid. The use ofalkanoic acids other than acetic affords the corresponding Son-(loweralkanoates). Selective hydrolysis of the 3-acyloxy group and also the 17-acyloxy group, in those intermediates containing the lattersubstituent, without affecting the 5a- (lower alkanoyl)oxy moiety iseffected by means of mineral acid such as hydrochloric or sulfuric acidor by basic reagents such as potassium carbonate in apolar anhydroussolvent medium. Lower alkanols such as methanol are particularlysuitable. In that manner, 3B,5u-diacetoxy-6B,19-epoxyandrostan-17-one iscontacted with hydrogen chloride in methanol to atford50cacetoxy-6B,l9-epoxy-3,B-hydroxyandrostan-17-one. Oxidation of those5ot-acetoxy-6fl,l9-epoxy-3fi-ols carrying either a 17fi-hydroxy or17-oxo substituent, suitably with chromium trioxide and aqueous sulfuricacid in acetone, results in 5a-acet0xy-65,19-epoxyandrostane-3,l7-dione.Conversion of that precursor directly to the desired 19-hydroxyandrost-4-ene-3,17-dione is accomplished by heating with amixture of zinc and zinc chloride in ethanol. An alternate route forconversion of the 3fi,50z-Cll-(lOW61 alkanoyl)oxy-6fl,19-epoxyintermediates to l9-hydroxyandrost-4-ene-3,l7-dione involves heatingwith aqueous sodium hydroxide in methanol to effect hydrolysis of bothester groups, oxidation of the resulting Ilfl,5oa-dihydroxy substancewith chromic acid to yield 613,19-epoxy-5a-hydroxyandrostane-3,17-dioneand reaction of the latter precursor with zinc and zinc chloride toafford the desired end product.

An alternate scheme for producing the instant Set-acetoxy-6fi,19-epoxyintermediates involves the consecutive steps of epoxidation with anorganic peracid such as peracetic or perbenzoic acid of the startingmaterials of the formula wherein R is hydrogen or a lower alkanoylradical and X is a carbonyl, ketalized carbonyl, or fl-(lower alkanoyl)oxyrnethylene group, followed by cleavage of the resulting epimericmixture of 5,6-epoxides to afford the 3B,50c,6fltriol, acylation ofthose triols with acetic acid and acetic anhydride in the presence ofp-toluene-sulfonic acid to produce the 3fl,5a,6B-triacetoxy derivative,selective hydrolysis of the 3-and -acetoxy groups by heating with abasic reagent such as tetramethylguanidine, potassium carbonate, orsodium carbonate in an anhydrous polar medium such as a lower alkanol,for example methanol, selective acylation of the 3-hydroxy group of theresulting 3;3,6p-dihydroxy compound, for example with acetic acid andacetic anhydride in pyridine, and oxidation with lead tetraacetate andiodine of the resulting 35,5u-diacetoxy-Gfl-hydroxy compound. By thatsequence of reactions, BB-acetoxyandrost-S-en-17-one, for example, isconverted to 3B,5u diacetoxy-GB,l9-epoxyandrostan-17- one.

19-hydroxyandrost-4-ene-3,17dione is useful as an intermediate in knownprocesses for the production of useful 19-norsteroids. Thus, oxidationof the hydroxy group, typically with chromium trioxide, results inIOB-carboxyestr-4-ene-3,17-dione, which is decarboxylated by reactionwith pyridine to afford estr-5(10)-ene3,l.7-dione. Conversion of thelatter diketone to the 3dimethyl ketal followed by ethynylation of thel7-keto group and mild cleavage of the ketal function with a reagentsuch as malonic acid results in l7a-ethynyl-17fl-hydroxestr-5 (l0)-(lower alkyl) 0 wherein R is a lower alkyl or lower alkynyl radical.Utilization of those starting materials affords the 19-hydroxy compoundsof the formula OH CH3 OH CE: I R

Y which can be converted to the corresponding 19-nor compounds by themethods described above. The latter 19- hydroxy intermediates can beproduced alternatively from the instant 6,8,19-epoxy intermediates. Theintermediates suitable for that purpose are6,8,19-epoxy-3flfia-dihydroxyandrostan-l7-one and the corresponding5-mono- (lower alkanoates). As a specific example, the S-acetate isallowed to react with acetylene in the presence of potassiumtertiary-pentoxide, and the resulting 17a-ethynyl- 17fi-hydroxyderivative is oxidized with chromium trioxide to aiford 65,19 epoxy-17a-ethynyl-5a,17B-dihydroxyandrostan-3-one. The 5or-hydroxy intermediateis, however, the preferred starting material for production of thelatter product. Cleavage of that 65,19-epoxide with zinc and zincchloride by the procedure hereinbefore described affordsl7a-ethynyl,l7fi,19-dihydroxyandrost-4-en- 3-one.

This application is a continuation-in-part of our copending applicationSerial No. 288,881, filed June 19, 1963, and now abandoned.

The invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only, and it will beunderstood that the invention is not to be construed as limited inspirit or in scope by the details contained therein as manymodifications in materials and methods will be apparent from thisdisclosure to those skilled in the art. In these examples, temperaturesare given in degrees centigrade C.). Quantities of materials areexpressed in parts by weight unless otherwise noted.

Example I A mixture of 9.5 parts of 5,6,6/3-epoxyandrostane-3fi,

. 17fl-diol 3,l7diacetate, 21 parts of acetic acid, and 0.2

part of p-toluenesulfonic acid is kept at room temperature for about 64hours, then is diluted with a mixture of ice and water. The precipitatewhich forms is collected by filtration, and the filter cake is washedfirst with a mixture of ether and water, then with acetone to atiordandrostane- 3 ,8,5 or,6fl,17,8-tetrol 3,5 ,17-triacetate, melting atabout 213- 223 Recrystallation from a mixture of benzene and etheraffords the pure material, melting at about 23 7-239 Example 2 A mixtureof 3.45 parts of androstane-3B,5a,6p,17fltetrol 3,5,17-triacetate, 10.2parts of lead tetraacetate, 3.9 parts of iodine, and 48 parts of carbontetrachloride, in an atmosphere of nitrogen, is heated at the refluxtemperature for about 8 hours. This reaction mixture is cooled andfiltered, and the filtrate is washed successively with aqueous sodiumiodide, aqueous sodium sulfite, and water, then dried over anhydroussodium sulfate and stripped of solvent at reduced pressure.Recrystallization of the residue from hexane affords pure6,8,19-epoxyandrostane-3fl,5a,l7B-triol 3,5,17-triacetate, melting atabout 161163 and characterized also by the structural formula CRCOCHQOCOCH;

CHaCOO Example 3 To a warm solution of 3.9 parts of513,6,8-epoxyandrotane-3fi,l7[a-di0l 3,17-diacetate and 2.54 parts ofiodine in 42 parts of acetic acid is added 8.6 parts of leadtetraacetate with stirring, and the resulting reaction mixture is heatedto approximately 65 and maintained at that temperature for about onehour. At the end of that time, an additional 4.3 parts of leadtetraacetate is added, and heating at approximately 65 is continued forabout 1% hours longer. The reaction mixture is cooled to roomtemperature, then is diluted with approximately 200 parts by volume of a1:1 ether-benzene solution. To that solution is added 25 parts of zinc,and stirring is continued for about 2 hours. Removal of the yellowsolids by filtration affords a filtrate which is washed successivelywith dilute aqueous potassium bicarbonate and aqueous sodiumthiosulfate, then dried over anhydrous sodium sulfate and concentratedto an oily residue under reduced pressure. Recrystallization of thatresidue from aqueous methanol aitords crystalline6B,19-cpoXyandrostane-3B,5a,17B-triol 3,5,l7-triacetate, identical withthe product of Example 2.

Example 4 A mixture of 18 parts of3fl-acetoxy-55,6/3-epoxyandrostan-l7-one, 37.8 parts of acetic acid, and0.18 part of p-toluenesulfonic acid is stirred at room temperature forabout 21 hours, then is diluted with water. The resulting solid whichseparates is collected by filtration, washed with water, and dried.Recrystallization of this material from a mixture of acetone and hexaneproduces pure 3/3,Str-diaCetoXy-GB-hydroxyandrostan-17-one, which sub-=stance melts at about 226-229".

Example 5 A mixture of 26 parts of3,8,5a-diacetoxy-6B-hydroxyandrostan-l7-one, 59.2 parts of leadtetraacetate, 25.6 parts of iodine, and 1600 parts of carbontetrachloride is stirred and heated at the reflux temperature for about8 hours. The reaction mixture is cooled, and the insoluble material isremoved by filtration. The filtrate is washed with aqueous sodiumthiosulfate, then is dried over anhydrous sodium sulfate andconcentrated to an oil at reduced pressure. This oil is crystallizedfrom a mixture of methylene chloride and hexane to yield3,8,5or-diacearmpit toxy-Gfl,19-epoxyandrostan-17-one, melting at about112- 114". It is represented by the structural formula CHsC 00 3 COCHExample 6 'The substitution of an equivalent quantity ofZip-acetoxy-513,6,8-epoxyandrostan-l7-one in the procedure of Example 3results in 3/3,5a-diacetoxy-6B,l9-epoxyandrostan-17-one, identical withthe product of Example 5.

Example 7 Example 8 To a solution of 1.5 parts of6fi,l9-epoxy-3;8,5oc,17fltriol 3,5,l7-triacetate and 64 parts ofmethanol is added a solution of 3 parts of sodium hydroxide in 20 par-tsof water. This reaction mixture is heated, under nitrogen, at the refluxtemperature for about 1% hours, then is stripped of solvent at reducedpressure. The residue is Washed with a mixture of Water and chloroform,then is collected by filtration to yield 6/3,l9-epoxyandrostane-3fl,5ot,l7fl-triol, melting at about 259-261". This compound isrepresented by the structural formula Example To a solution of 6 partsof 65,19-epoxyandrostane- BB,5a, 17,81triol in 400 parts of acetone isadded an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuricacid, until excess reagent is present. To this mixture is then added onepart of isopropyl alcohol in order to destroy the excess reagent.Removal of the solvent by distillation at reduced pressure affords aresidue which is stirred with a mixture of water and chloroform. The

chloroform layer is separated, then washed successively with aqueoussodium hydroxide and water. Drying over anyhdrous sodium sulfatefollowed by distillation of the solvent at reduced pressure affords acrystalline residue which is triturated with ether to yield6fi,19-epoxy-5ahydroxyandrostane-3,17-dione, melting at about 254.5- 260and represented by the structural formula Example 11 A mixture of 2parts of 3 8,5a-diacetoxy-65,19-epoxy- Iandrostan-N-one, 5 parts ofpotassium carbonate, 64 parts of methanol, and 20 parts of Water isstirred at room temperature for about 60 hours. The organic solvent isremoved by distillation at reduced pressure, and approximately 30 partsof water is added. The resulting solid is collected by filtration,washed on the filter with water, and dried to yield 613,19-epoxy-38,5a-dihydroxyandrostan- 17-one, melting at about 270-272 andrepresented by the structural formula Example 12 To a solution of 44.5parts of 3/3,5a-diacetoxy-6,3,19- epoxyandrostan-17-one in 176 parts ofmethanol is added 17.5 parts by volume of a 15% isopropanolic hydrogenchloride solution, and the resulting reaction mixture is stirred at roomtemperature for about 4 hours. Approximately /2 of the methanol isremoved by distillation at reduced pressure, and the residual solutionis diluted by the addition of approximately 200 parts of water. Furtherconcentration of the solution at reduced pressure results incrystallization of the crude product which is collected by filtrationand dried. That material melts at about then resolidifies and meltsagain at about -l60. Recrystallization from methylene chloridehexaneaffords pure 5a-acetoxy-6fl,19-epoxy-3B-hydroxyandrostan-17-one, whichdisplays a melting point at about 157-462 and is further characterizedby the structural formula ooooH3 Example 13 17-one in 468 parts ofacetone is added dropwise, over a period of about 10 minutes, 34 partsby volume of an aqueous solution, 8 N in chromium trioxide and 8 N insulfuric acid. The resulting reaction mixture is stirred for about 5minutes, at the end or" which time a small quantity of isopropanol isadded in order to destroy the excess unreacted oxidant. A portion of thesolvent is removed by distillation at reduced pressure, and the residualmixture is diluted with approximately 150 parts of water. The solidwhich precipitates is collected by filtration, Washed with Water, anddried to afford the crude product, melting at about 199-2023Recrystallization from acetone-hexane results in SOt-aCCtOX-6fl,19-epoxyandrostane- 3,17-dione, melting at about 202-204", andrepresented by the structural formula I I OCOCHa Example 14 To a mixtureof 5 parts of 5ot-acetoxy-6BJ9-epoxyandrostane-3,17-dione, 5 parts ofZinc, and 63 parts of ethanol is added dropwise, with stirring at thereflux temperature, a solution of parts of zinc chloride in 24 parts ofethanol over a period of about minutes. Heating of that reaction mixtureat the reflux temperature for about 1 /2 hours is followed by filtrationin order to remove unchanged zinc. The solvent is removed bydistillation at reduced pressure, and the residue is diluted with water,then extracted with chloroform. The organic layer is separated, washedwith dilute hydrochloric acid, dried over anhydrous sodium sulfate, andstripped or" solvent by distillation at reduced pressure. Thecrystalline residue is recrystallized from methylene chlorideethylacetate to afford pure 19-hydroxyandrost-4-ene-3,l7-dione, melting atabout 169-170".

Example To a mixture of 0.08 part of p-toluenesulfonic acid in 16 partsof methanol is added 10 parts of 3/3-acetoxy-5B,6/3-epoxyaudrostan-17-one, and this reaction mixture is stirred at roomtemperature for about 15 minutes. At

the end of this time, an additional 0.08 part of p-toluene-.

sulfonic acid and approximately 3 parts of methanol are added, andstirring is continued for about 15 minutes longer in order to achievecomplete solution. The reaction mixture is diluted with water andextracted with ethyl acetate. The ethyl acetate layer is separated,washed with dilute aqueous potassium bicarbonate, dried over anhydroussodium sulfate and concentrated to dryness under reduced pressure toafford a crystalline residue. Recrystallization from a mixture ofmethylene chloride, hexane, and ether yields pure3B-acetoxy-6/3-hydroxy-5ctmethoxyandrostan-l7-one, melting at about201-203".

Example 16 A mixture of 5 parts of 5p,6p-epoxyandrostane-3p,17pdiol3,17-diacetate, 0.04 part of p-toluenesulfonic acid monohydrate, and 8parts of methanol is stirred at room temperature for about 10 minutes,then is warmed to about 40-45" and is stirred for about 5 minuteslonger. The reaction mixture is then cooled, an additional 0.04 part ofp-toluenesulfonic acid monohydrate is added, and this mixture is stirredat room temperature for about 15 minutes. Dilution with benzene affordsan organic solution which is washed successively with dilute aqueouspotassium carbonate and water, is dried over anhydrous sodium sulfate,then is evaporated to dryness under reduced pressure. Recrystallizationof the resulting residue from ether results in pure5a-methoxyandrostane-3,8,65, l7fl-triol 3,-17-diacetate, melting atabout fill-206.

Example 17 The substitution of 10.2 parts of 513,6{3-ep0xyandrostane-3fl,17/3-diol 3,17-dipropionate in the procedure of Example 1 results in5oc-acetoxyandrostane-3,8,65,17(3-triol 3,17- dipropionate.

Example 18 By substituting 3.66 parts of 5a-acetoxyandrostane3,8,6',17,3-trio1 3,17-dipropionate and otherwise proceeding accordingto the processes of Example 2, 5ot-acetoxy 6B,l9-epoxyaudrostane-3fi,l7fl-diol 3,17-dipropionate is obtained.

Example 19 The substitution of 1.6 parts of SOC-RCCtOXY-6By19-6POXY-androstane-3fl,17fl-diol 3,17-dipropion1te in the procedure of Example 9alfords 6,8,19-epoxyandrostane-3B,5a,17f triol, identical with theproduct of that example.

Example 20 By substituting 18.7 parts of5fi,6,B-epoXy-3,8-propionoxyandrostan-17-one and otherwise proceedingaccording to the processes of Example 4, 5a-acetoxy-6fi-hydroxy-3,B-propionoxyandrostan-17-one is obtained.

Example 21 The substitution of 26.9 parts of5u-acetoxy-6B-hydroxy-3fl-propionoxyandrostam17-0ne in the procedure ofExample 5 results in5oc-acetoxy-6fl,l9-epoxy-3fi-propionoxyandrostan-l7-one.

Example 22 By substituting an equivalent quantity of androstane-3p,5a,6fi,17/3-tetro1 3,5,6,17-tetraacetate and otherwise proceedingaccording to the procedure described in Example 7,androstane-3fi,5u,6;8,17/3-tetrol S-acetate is obtained.

Example 24 The substitution of an equivalent quantity ofandrostane-3fi,5a,6,8,17(3-tetrol S-acetate in the procedure of Example8 results in androstane-3fl,5a,6,B,17fl-tetrol 3,5, 17-triacetate.

Example 25 By substituting an equivalent quantity of androstane-3,8,5ot,6fl,17B-tetrol 3,5,17-triaceate and otherwise proceedingaccording to the processes described in Example 5,6,8,19-epoxyandrostane-3p,5a,17,8-triol 3,5,17-triacetate is obtained.

Example 26 The hydrolysis of an equivalent quantity of6fl,19-epoxyandrostane-3,6,5ot,17fi-triol 3,5,17-triacetate according tothe procedure of Example 12 afiords 5ot-acetoxy-6B,19-epoxyandrostane-Bfl,17/3-diol.

Example 27 An equivalent quantity of5a-acetoxy-6fl,19-epoxyandrostane-3;3,17,8-diol is oxidized according tothe procedure described in Example 13 to afford 5ot-acetoxy-6fl,l9-epoxyandrostane-3,17-dione, identical with the product of that example.r

9 Example 28 By substituting an equivalent quantity of55,6fi-epoxyandrostane-3B,17;3-di0l 3,17-dipropionate and otherwiseproceeding according to the processes described in Example 3,5a-acetoxy-6fl,l9-epoxyandrostane-3fi,17p-diol 3,17-dipropionate isobtained.

Example 29 By substituting an equivalent quantity of Sa-acetoxy-6/3,l9-epoxyandrostane-3B,17,8-di01 3,17-dipropionate and otherwiseproceeding according to the processes of Example 12,5a-acetoxy-6;3,19-epoxyandrostane-3fi,l7fl-dio1 is obtained.

Example 30 To 101 parts of tertiary-amyl alcohol is added, in a nitrogenatmosphere at the reflux temperature, 10 parts of potassium, andrefluxing is continued until solution is complete. This solution iscooled to about 5 and the resulting suspension of potassiumtertiary-pentoxide is diluted with an equal volume of ether. Acetylenegas is passed into the mixture for about 30 minutes, after which time 10parts of 6B,l9-epoxy-3,B,Sa-dihydroXyandrostan-17-one is added. Theaddition or" acetylene is con. tinued for about 3 hours longer, and thisreaction mixture is then stored at -5 for about 16 hours. To thatmixture is added approximately 100 parts of 10% aqueous ammoniumchloride, and the tertiary-amyl alcohol is removed by steamdistillation. The solid which separates is collected by filtration,washed with water, and dried. Recrystallization from methanol-ethylacetate produces pure 6 5, 19-epoxy- 17 a-ethynylandrOstane-Z ,8,5 or,17,8-triol, melting at about 285287.

Example 31 By substituting an equivalent quantity of a-acetoxy-6e,19-epoxy-3e-hydroxyandrostan-17-one and otherwise proceedingaccording to the processes of Example 30, 6s, 19 epoxy 17aethynylandrostane-3B,5a,17,8-triol is ob tained.

Example 32 To a solution of 3 parts of6/3,19-epoxy-l7a-ethynylandrostane-35,5a,17[3-triol in 160 parts ofacetone is added approximately 3 parts by volume of an aqueous solution,8 N in chromium trioxide and 8 N in sulfuric acid, until an excess ofthe oxidant is present. Approximately 2.4 parts of isopropyl alcohol isthen added to destroy the excess oxidizing agent, and the solvents areremoved by distillation at reduced pressure. The resulting mixture isdiluted with water, and the solid material is collected by filtration,then washed and dried. Recrystallization from a mixture oftetrahydrofuran and ethyl acetate results in pure6B,19-epoxy-17a-ethynyl-5rx,17/8-dihydroxyandrostan-3-one, melting atabout 295-300.

Example 33 The substitution of an equivalent quantity of 6,8,19- epoxy17oz ethynyl 50:,175 dihydroxyandrostan 3- one in the procedure ofExample 14 results in 170:- ethynyl-17,8,19-dihydroxyandrost4-en-3-one.

xample 34 A mixture of 15 parts of5a-acetoxy-3B.6fi-dihydroxyandrostan-l7-one, 1.5 parts ofp-toluenesulfonic acid, and 47.3 parts of acetic acid is stirred at roomtemperature for about 36 hours. The reaction mixture is diluted withapproximately 250 parts of water, and the precipitate which forms iscollected by filtration, dried, then recrystallized from methylenechloride-hexane to yield 313,5a-diacetoxy-6fl-hydroxyandrostan-17-one,identical with the product of Example 4.

10 What is claimed is: 1. A process for the manufactiure of19-hydroxyandrost-4-ene-3,17-dione which comprises the steps ofcontacting a compound of the formula CH CH 0 (lower alkyl) (ii 0 whereinX is selected from the group consisting of carbonyl and p-(loweralkanoyl)oxymethylene, with acetic acid in the presence of an acidcatalyst, contacting the resulting l7-oxygenated5a-acetoxyandrostane-3fi,6B-diol 3-(lower alkanoate) with leadtetraacetate to afford the corresponding 17-oxygenated5aacetoxy-6fi,l9-epoxyandrostan-3fi-ol 3-(lower alkanoate), electivelyhydrolyzing the latter substance with an acidic or alkaline reagent,contacting the resulting 17-oxygenated 5ot-acetoxy-6fl,19-epoxyandrostan-Zfi-ol with chromic acid to aiford5aacetoxy-6B,19-epoxyandrostane-3,17-dione, and contacting that dionewith a mixture of zinc and zinc chloride.

2. The process of claim 1, wherein the lower alkyl group is methyl andthe group symbolized by X is fi-acetoxymethylene.

3. The process of claim 1, wherein the lower alkyl group is methyl andthe group symbolized by X is carbony 4. A process for, the manufactureof 19-hydroxyandrost-4-ene-3,17-dione which comprises the steps ofselectively hydrolyzing a compound of the formula wherein X is selectedfrom the group consisting of carbonyl and B-acetoxymethylene, bycontacting that compound with an alkaline reagent in an anhydrousorganic solvent medium, selectively acylating the resulting17-oxygenated 5a-acetoxyandrostane-Bfi,6B-dio1 with an acetylatingagent, contacting the resulting 17-oxygenated an-'drostane-3/3,5a,6fi-triol 3,5-diacetate with lead tetraacetate toafiord the corresponding 17-oxygenated6,8,19-epoxyandrostane-Iafija-diol 3,5-diacetate, selectivelyhydrolyzing the latter substance with an acidic or alkaline reagent,contacting the resulting 17-oxygenated 5a-acetoxy-6BJ9-epoxyandrostan-3B-ol with chromic acid to aflord5aacetoxy-6,B,19-epoxyandrostane-3,17-dione, and contacting that dionewith a mixture of zinc and zinc chloride.

5. The process of claim 4 wherein the group symbolized by X isfl-acetoxymethylene.

6. The process of claim 4 wherein the group symbolized by X is carbonyl.

7. A process for the manufacture of l9-hydroxyandrost- 4-ene-3,17-dionewhich comprises the steps of contacting a compound of the formula CH CH3(lower alkyl) ii 0- wherein X is selected from the group consisting ofcarbonyl and ,B(lower alkanoyDoxymethylene, with lead tetraace tate toafford the corresponding l7-oxygenateda-acetoXy-6fl,19-epoXyandrostan-3B-ol 3-(lower alkanoate), selectivelyhydrolyzing the latter substance with an acidic or alkaline reagent,contacting the resulting l7- oxygenatedSa-acetoxy6,8,19-epoXyandrostan-3fi-ol with chromic acid to afford5a-acetoxy-6fl,l9-epoxyandrostane- 3,l 7-clione, and contacting thatdione With a mixture of zinc and zinc chloride.

8. The process of claim 7 wherein the lower alkyl group is methyl andthe group symbolized by X is ,B-acetoxymethylene.

9. The process of claim 7 wherein the lower alkyl group is methyl andthe group symbolized by X is carbonyl.

10. A process for the manufacture of 19-hydr0xyandrost-4-ene-3,l7-dionewhich comprises the steps of contacting :a compound of the formula C H;0 H3 i 7 (lower alk no 0 wherein X is a radical selected from the groupconsisting of carbonyl and fl-(lower alkanoyl)oxymethylene,

with acetic acid in the presence of an acid catalyst, contacting theresulting 17-oxygenated 5oc-acetoxyandrostane- 3;3,66-diol 3-(loweralkanoate) with lead tetraacetate to yield the corresponding17-oxygenated SOC-flCtOXY-6fi, 19-epoxyandrostan-3/3-ol 3-(lo-Weralkanoate), hydrolyzing the latter substance with an alkaline reagent,contacting the resulting l7-oxy genated65,19-epoxyandrostane-3/3,5a-diol with chromic acid to yield65,19-epoxy- 5a-hydroxyandrostane-3,l7-dione, and reacting thatsubstance with zinc and zinc chloride.

11. The process of claim 10, wherein the lower alkyl group is methyl andthe group symbolized by X is B- acetoxymethylene.

12. The process of claim 10, wherein the lower alkyl group is methyl andthe group symbolized by X is carbonyl.

13. A compound of the formula References Cited in the file of thispatent UNITED STATES PATENTS 3,001,989 Ringold et al. Sept. 26, 1961OTHER REFERENCES Berkoz et aL: Steroids, vol. 1, No. 3, March 1963,

pp. 251270i

13. A COMPOUND OF THE FORMULA